Frontline Immunotherapy Combinations for NSCLC

Mark A. Socinski, MD: Roy, it’s obviously very exciting data that we’re talking about. But it seems to me that, as we do with most things, we want to potentially move [immune checkpoint inhibitors] to the first-line setting. Give us your thoughts about use in the first-line. I know we have a number of clinical trials ongoing.

Roy S. Herbst, MD, PhD: Certainly! The idea of bringing immunotherapy to the frontline setting is where the drugs are really going to differentiate themselves. If we could use an immunotherapy drug and have results like we’re seeing in the second-line setting, perhaps even greater, and not have the side effects of chemotherapy, that would be wonderful. What’s happening now is that all the different agents that are under study, PD-L1 agents and PD-1 agents, are moving to the frontline setting.

There are a number of different trial designs. Generally, most groups are using whatever biomarker they’ve chosen to select the higher group of responders. Those are being used to select patients in the frontline. I’m very partial to trials that are looking at chemotherapy versus a PD-1 or PD-L1 agent with some kind of biomarker selection. Of course, each of the groups has a different biomarker selection.

The other approach, of course, is combination with chemotherapy; that’s what we do. Now, will that be better or not? How does that play? Some of you might give chemotherapy. You might give the PD-1 or PD-L1 agent. You might give an angiogenesis inhibitor, maybe even bevacizumab. Some data are mixed.

There are some data with nivolumab that don’t look so exciting and, actually, Naiyer can probably comment better than I can, as he presented some of those. Then, there’s the data with the atezolizumab which looks rather exciting. However, I would caution, having done this long enough and I’m sure you’ve seen the same, that you can always get high response rates with selected patients in a phase II trial with chemotherapy plus a novel drug.

I’m particularly intrigued by combining bevacizumab with the atezolizumab or chemotherapy because I think that angiogenesis might traffic more T-cells into the tumor. We need a little bit more data on that, but there are some randomized trials ongoing there, as well.

The promise of having this drug available to, perhaps, 30% of people in the frontline setting is huge. For those patients that do not have the right profile, we need to think of using combinations. The other thing about biopsies in the frontline setting is that there is less variability because you’ve got a biopsy that is much closer to the time that you’re treating; it’s first-line and there’s been no prior treatment.

Mark A. Socinski, MD: Naiyer, any comments?

Naiyer Rizvi, MD: We don’t really know what the potentially deleterious effects are in terms of chemotherapy on your T-cells or your immune system and whether you’re harming them in some way. The first-line data will be really important. We’re a part of both the nivolumab and the pembrolizumab first-line experiences, and if you look at the waterfall plot for pembrolizumab, for example, there are very few patients that didn’t have some level of tumor regression.

There’s no question that there’s going to be a subset of patients that will be positioned to get single-agent first-line therapy. Again, as we come back to the biomarker, I think that’s probably where it’s going to be most useful. As you know, there are randomized trials in PD-L1-positive patients with PD-1 inhibitors versus chemotherapy. Those trials will be very useful when they read out to help make that decision.

The other piece in first-line therapy is combination immunotherapy with CTLA-4 and PD-1 or CTLA-4 and PD-L1. We’ve seen the data in melanoma which showed a clear superiority with combination immunotherapy, both in PD-L1-positive as well as -negative patients. And so if you have lung cancer and half of the patients are PD-L1-negative, you want to do more for those patients. Maybe those tumors are less mutated or have lower levels of PD-L1. Can we drive greater immune recognition and T-cell response with the CTLA-4, or PD-1, or PD-L1 combination?

CTLA-4 does more priming of T-cells within lymph nodes, whereas, PD-1 and PD-L1 cause more activation within the tumor microenvironment. It makes sense to combine them. Certainly, the preliminary data do look like you could get some reasonable activity in both PD-L1-positive and -negative tumors.

The data with MEDI4736 [anti-PD-L1] and tremelimumab [anti-CTLA-4] showed about a 30% response rate, whether you’re PD-L1-positive or -negative. That combination, as well as the nivolumab and ipilimumab combination, are both in phase III trials now as first-line combinations versus single-agent immunotherapy versus chemotherapy. We’re just starting to figure this out. I think we’re going to learn a lot as we go along.

Mark A. Socinski, MD: Your point, at least to me, is that the use of a biomarker is critically important in the first-line. It’s like the EGFR story. If you use an EGFR TKI in the mutant population first-line, it’s much better than the standard.

Geoffrey R. Oxnard, MD: Once the biomarker catches on in the first-line, you wonder if it might catch on in all sorts of places.

Mark A. Socinski, MD: Independent of the biomarker and other than the usual exclusion criteria, and knowing what we know about the two CHECKMATE trials, where in squamous cell tumors the biomarker didn’t make a difference. In the nonsquamous tumors, even if you were biomarker-negative, you weren’t worse than with chemotherapy. I want to ask you guys about toxicity in a second. But, if you had a patient with this disease in the second- or third-line setting, with nonsquamous histology, which drug would you rather get, docetaxel or nivolumab?

Naiyer Rizvi, MD: I think the answer is nivolumab. What I would caution people about, though, is that the patients who respond are a subset of 20%. There’s this desire out there to grasp the concept of pseudoprogression as a huge deal and the patients don’t want to come off of the immunotherapy. The doctors don’t want to take them off in case the patient is having pseudoprogression. I think pseudoprogression occurs so infrequently in lung cancer patients. I’d hate to see patients kept on immunotherapy for too long and then not get to third-line chemotherapy.

Geoffrey R. Oxnard, MD: Which can work for a long time with the right people as well.

Naiyer Rizvi, MD: Right.

Transcript Edited for Clarity

Transcript:

Mark A. Socinski, MD: Roy, it’s obviously very exciting data that we’re talking about. But it seems to me that, as we do with most things, we want to potentially move [immune checkpoint inhibitors] to the first-line setting. Give us your thoughts about use in the first-line. I know we have a number of clinical trials ongoing.

Roy S. Herbst, MD, PhD: Certainly! The idea of bringing immunotherapy to the frontline setting is where the drugs are really going to differentiate themselves. If we could use an immunotherapy drug and have results like we’re seeing in the second-line setting, perhaps even greater, and not have the side effects of chemotherapy, that would be wonderful. What’s happening now is that all the different agents that are under study, PD-L1 agents and PD-1 agents, are moving to the frontline setting.

There are a number of different trial designs. Generally, most groups are using whatever biomarker they’ve chosen to select the higher group of responders. Those are being used to select patients in the frontline. I’m very partial to trials that are looking at chemotherapy versus a PD-1 or PD-L1 agent with some kind of biomarker selection. Of course, each of the groups has a different biomarker selection.

The other approach, of course, is combination with chemotherapy; that’s what we do. Now, will that be better or not? How does that play? Some of you might give chemotherapy. You might give the PD-1 or PD-L1 agent. You might give an angiogenesis inhibitor, maybe even bevacizumab. Some data are mixed.

There are some data with nivolumab that don’t look so exciting and, actually, Naiyer can probably comment better than I can, as he presented some of those. Then, there’s the data with the atezolizumab which looks rather exciting. However, I would caution, having done this long enough and I’m sure you’ve seen the same, that you can always get high response rates with selected patients in a phase II trial with chemotherapy plus a novel drug.

I’m particularly intrigued by combining bevacizumab with the atezolizumab or chemotherapy because I think that angiogenesis might traffic more T-cells into the tumor. We need a little bit more data on that, but there are some randomized trials ongoing there, as well.

The promise of having this drug available to, perhaps, 30% of people in the frontline setting is huge. For those patients that do not have the right profile, we need to think of using combinations. The other thing about biopsies in the frontline setting is that there is less variability because you’ve got a biopsy that is much closer to the time that you’re treating; it’s first-line and there’s been no prior treatment.

Mark A. Socinski, MD: Naiyer, any comments?

Naiyer Rizvi, MD: We don’t really know what the potentially deleterious effects are in terms of chemotherapy on your T-cells or your immune system and whether you’re harming them in some way. The first-line data will be really important. We’re a part of both the nivolumab and the pembrolizumab first-line experiences, and if you look at the waterfall plot for pembrolizumab, for example, there are very few patients that didn’t have some level of tumor regression.

There’s no question that there’s going to be a subset of patients that will be positioned to get single-agent first-line therapy. Again, as we come back to the biomarker, I think that’s probably where it’s going to be most useful. As you know, there are randomized trials in PD-L1-positive patients with PD-1 inhibitors versus chemotherapy. Those trials will be very useful when they read out to help make that decision.

The other piece in first-line therapy is combination immunotherapy with CTLA-4 and PD-1 or CTLA-4 and PD-L1. We’ve seen the data in melanoma which showed a clear superiority with combination immunotherapy, both in PD-L1-positive as well as -negative patients. And so if you have lung cancer and half of the patients are PD-L1-negative, you want to do more for those patients. Maybe those tumors are less mutated or have lower levels of PD-L1. Can we drive greater immune recognition and T-cell response with the CTLA-4, or PD-1, or PD-L1 combination?

CTLA-4 does more priming of T-cells within lymph nodes, whereas, PD-1 and PD-L1 cause more activation within the tumor microenvironment. It makes sense to combine them. Certainly, the preliminary data do look like you could get some reasonable activity in both PD-L1-positive and -negative tumors.

The data with MEDI4736 [anti-PD-L1] and tremelimumab [anti-CTLA-4] showed about a 30% response rate, whether you’re PD-L1-positive or -negative. That combination, as well as the nivolumab and ipilimumab combination, are both in phase III trials now as first-line combinations versus single-agent immunotherapy versus chemotherapy. We’re just starting to figure this out. I think we’re going to learn a lot as we go along.

Mark A. Socinski, MD: Your point, at least to me, is that the use of a biomarker is critically important in the first-line. It’s like the EGFR story. If you use an EGFR TKI in the mutant population first-line, it’s much better than the standard.

Geoffrey R. Oxnard, MD: Once the biomarker catches on in the first-line, you wonder if it might catch on in all sorts of places.

Mark A. Socinski, MD: Independent of the biomarker and other than the usual exclusion criteria, and knowing what we know about the two CHECKMATE trials, where in squamous cell tumors the biomarker didn’t make a difference. In the nonsquamous tumors, even if you were biomarker-negative, you weren’t worse than with chemotherapy. I want to ask you guys about toxicity in a second. But, if you had a patient with this disease in the second- or third-line setting, with nonsquamous histology, which drug would you rather get, docetaxel or nivolumab?

Naiyer Rizvi, MD: I think the answer is nivolumab. What I would caution people about, though, is that the patients who respond are a subset of 20%. There’s this desire out there to grasp the concept of pseudoprogression as a huge deal and the patients don’t want to come off of the immunotherapy. The doctors don’t want to take them off in case the patient is having pseudoprogression. I think pseudoprogression occurs so infrequently in lung cancer patients. I’d hate to see patients kept on immunotherapy for too long and then not get to third-line chemotherapy.

Geoffrey R. Oxnard, MD: Which can work for a long time with the right people as well.